Epoxomicin and Eponemycin, depicted below, are natural products isolated from unidentified actinomycete strain No. Q996-17 and from streptomyces thiogroscopicus No. P247-271, respectively (see, Hanada et al. J. Antibiotics 1992, 45, 1746-1752; Sugawara et al. J. Antibiotics 1990, 43, 8-18) that exhibit anti-tumor, and, in the case of epoxomicin, anti-inflammatory activity. Interestingly, both of these compounds have also been shown to bind covalently and irreversibly to the 20S proteasome (see, Sin et al. Bioorg. Med. Chem. Lett. 1999, 9, 2283-2288; Meng et al. Proc. Nail. Acad. Sci. USA 1999, 96, 10403-10408; Meng et al. Cancer Res. 1999, 59, 2798-2801).

The ability of these natural products and other compounds to act as proteasome inhibitors has attracted significant interest because of the wide range of cellular substrates and processes controlled or affected by the ubiquitin-proteasome pathway. For example, the oscillation of cyclins (cell cycle proteins required for the orderly progression through the cell cycle) has been found to be due to the regulated degradation mediated by the ubiquitin-proteasome pathway, and inhibition of this pathway is believed to result in the blockage of cell cycle progression. Additionally, the transcription factor NF-κB is another regulatory protein involved in a variety of cellular processes, including immune and inflammatory responses, apoptosis, and cellular proliferation, whose mode of action is controlled by the ubiquitin-proteasome pathway. Furthermore, it has also been shown that the ubiquitin-proteasome pathway is involved in retrovirus assembly and thus may be a useful target for the development of anti-HIV drugs. For a general discussion of the ubiquitin-proteasome pathway and proteasome inhibitors see, Myung et al. “The Ubiquitin-Proteasome Pathway and Proteasome Inhibitors” Medicinal Research Reviews 2001, 21, 245-273.
As a result of the ability of the epoxyketones epoxomicin and eponemycin to inhibit the proteasome, there has been interest in developing the therapeutic potential of this class of compounds. Examples of other linear peptide epoxyketones that have been isolated recently on the basis of proteasome inhibition screening from microbial metabolites include TMC-86A, TMC-86B, TC 1084, TMC-89A and TMC-89B (see, Koguchi et al. J. Antibiotics, 2000, 53, 63-65; Koguchi et al. J. Antibiotics 2000, 53, 967-972). Additionally, certain synthetic epoxyketones have been prepared and investigated (Elofsson et al. Chem. Biol. 1999, 6, 811-822). Although there has been significant interest in the development of epoxyketones as proteasome inhibitors useful as potential therapeutics, there remains a need to prepare and investigate the biological activity of a wider range of analogues of this class of compounds. Clearly, it would be desirable to develop analogues that are safe and efficacious for the treatment of cancer, immune or inflammatory disorders, or HIV, to name a few. Additionally, it would be desirable to develop analogues that specifically target the ubiquitin-proteasome pathway.